Abstract
Alcoholic cardiomyopathy (ACM) develops from long-term, excessive consumption of alcohol. Initially, ACM is asymptomatic but continued alcohol abuse leads to reductions in cardiac contractility, the onset of arrhythmias, chamber dilation and congestive heart failure. This study was carried out to examine the effects of chronic alcohol on basal and β-adrenergic-stimulated properties of Ca2+ transients during excitation-contraction (E-C) coupling. Rats were pair-fed DeCarli and Lieber control and alcohol liquid diets for 120 days prior to isolating left ventricular myocytes. Under basal conditions, there was no change in the amplitude of electrically-triggered [Ca2+]i transients (Control, 296±21nM vs. Alcoholic, 260±18 nM) or contraction (Control, 11.9±0.6 μm, Alcoholic,12.7±1.2 μm. However, a blunted inotropic response (increase over basal: Control, 90±19% vs. Alcoholic 39±10 %) was observed in the presence of submaximal isoproterenol stimulation. In addition, maximal isoproterenol and forskolin stimulation do not improve the inotropic response of the alcoholic myocytes, suggesting a functional impairment in the initial Ca2+ release steps of E-C coupling. Consistent with the reduced [Ca2+]i transient amplitude, the Ca2+ current (ICa,L) responses to isoproterenol were also markedly reduced in cardiomyocytes from alcohol-fed animals. Surprisingly, measurement of L-type calcium channel expression by dihydropyridine (DHP) binding and real-time PCR, revealed an increased number of DHP binding sites (Control Bmax = 197 ± 60 fmol/mg vs. Alcoholic Bmax = 335 ± 45 fmol/mg, P < 0.05) and α1C subunit expression (Alcoholic 2-ΔΔCt1.69 ± 0.03, Control 2-ΔΔCt0.96 ± 0.02, P< 0.0005), respectively. This loss of L-type calcium channel activity, accompanied by an increased channel expression with chronic alcohol consumption may be a precipitating factor in alcoholic heart disease, leading to the onset of other adaptive mechanisms and, eventually, the clinical syndrome of heart failure.
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